Sinteza novih biološki aktivnih amino supstituiranih tetracikličkih derivata imidazo[4,5-b]piridina

master's thesis

• Title (english): Synthesis of novel biologically active amino substituted tetracyclic imidazo[4,5-b]pyridines
• Author: Matej Kadić
• Mentor: Marijana Hranjec (mentor)
• Committee member: Marijana Hranjec (predsjednik povjerenstva)
• Committee member: Tatjana Gazivoda Kraljević (član povjerenstva)
• Committee member: Lidija Furač (član povjerenstva)
• Granter: University of Zagreb; Faculty of Chemical Engineering and Technology; Zagreb
• Defense date and country: 2019-09-19, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry

Abstract

Cilj ovog rada bio je sintetizirati nove amino supstituirane tetracikličke derivate imidazo[4,5-b]piridina te ispitati njihova spektroskopska svojstva kao i potencijalnu primjenu kao pH senzora. Za pripravu ciljanih spojeva korištene su klasične metode organske sinteze te sinteza potpomognuta mikrovalovima. Reakcijom kondenzacije 2,3-diamino-6-klorpiridina 1 i 2-cijanoacetamida 2 dobiven je ciklički produkt 2-(5-klor-1H-imidazo[4,5-b]piridin-2-il)acetonitril 3. Reakcijom kondenzacije cikličkog spoja 3 i 2-klor-benzaldehida 4 priređen je aciklički prekursor 5. Termičkom ciklizacijom acikličkog prekursora 5 priređena je smjesa regioizomera 6a i 6b iz kojih su, reakcijom aminiranja potpomognutog mikrovalovima, priređeni amino supstituirani tetraciklički derivati imidazo[4,5-b]piridina 7 – 14. Sinteza spoja 10 nije bila uspješna. Strukture svih novo priređenih spojeva potvrđene su 1H NMR i 13C NMR spektroskopijom, a strukture odvojenih regioizomera potvrđene su i korištenjem 2D NMR spektroskopije. Spektroskopska karakterizacija provedena je korištenjem UV/Vis i fluorimetrijske spektroskopije matičnih otopina regioizomera 7 i 8 u 11 organskih otapala različite polarnosti. Iz dobivenih rezultata može se uočiti značajan utjecaj otapala na spektroskopske karaketristike regioizomera. pH titracije provedene su u svrhu utvrđivanja potencijalne primjene priređenih regioizomera 7 i 8 kao optičkih senzora za detekciju pH. Iz dobivenih rezultata može se zaključiti da promjena pH vrijednosti pufera uzrokuje promjene u intenzitetu i valnoj duljini maksimuma apsorbancije. Priređenim spojevima ispitana je i antitumorska aktivnost in vitro na tri tumorske stanične linije i ne-tumorske stanične linije. Neki od derivata pokazali su vrlo izraženu antiproliferativnu aktivnost u nanomolarnim inhibitornim koncentracijama.

Abstract (english)

The intention of this study was to synthesize new amino substituted tetracyclic derivatives of imidazo[4,5-b]pyridines and to examine their spectroscopic properties as well as potential application as pH sensors. For the preparation of the target compounds, classical methods of organic synthesis as well as microwave-assisted synthesis were used. Cyclic product, 2-(5-chloro-1H-imidazo[4,5-b]pyridine-2-yl)acetonitrile 3, was prepared by condensation of 2,3-diamino-6-chloropyridine 1 with 2-cyanoacetamide 2. Due to the condensation of cyclic compound 3 with 2-chloro-benzaldehyde 4, an acyclic precursor 5 was synthesized. The thermal cyclization of the acyclic precursor 5 provided a mixture of regioisomers 6a and 6b. Amino substituted tetracyclic derivatives of imidazo[4,5-b]pyridine 7 – 14 were obtained via uncatalyzed microwave assisted amination of regioisomers 6a and 6b. Synthesis of compound 10 was not successful. The structures of all newly synthesizes compounds were confirmed by means of 1H NMR and 13C NMR spectroscopy. The structures of the separated regioisomers were confirmed utilizing 2D NMR spectroscopy. Spectroscopic characterization of regioisomers 7 and 8 was performed by using UV/Vis and fluorimetric spectroscopy in 11 organic solvents of different polarities. From the obtained results, significant influence of the solvent on the spectroscopic characteristics of regioisomers was observed. pH titrations were performed to determine the potential application of prepared regioisomers 7 and 8 as optical pH sensors. From the obtained results it can be concluded that the change of pH causes changes in the intensity and wavelengths of the maximum absorbance. Synthesized derivatives were tested also for their antiproliferative activity in vitro on three cancer cell lines and non-tumor cells. Some of the derivatives displayed very strong antiproliferative activity in nanomolar range of inhibitory concentrations.

• Keywords: imidazo[4 5-b]piridini; pH senzori; regioizomeri; UV/Vis i fluorimetrijska spektroskopija; antiproliferativna aktivnost in vitro
• Keywords (english): imidazo[4 5-b]pyridines; pH sensors; regioisomers; UV/Vis and fluorimetric spectroscopy; antiproliferative activity in vitro
• Language: croatian
• URN:NBN: urn:nbn:hr:149:082811
• Project: Number: IP-2018-01-4379; Title: Istraživanje antioksidativnog djelovanja benzazolskog skeleta u dizajnu novih antitumorskih agensa; Acronym: AntioxPot; Leader: Marijana Hranjec; Jurisdiction: Croatia; Funder: HRZZ; Funding stream: IP
• Project: Number: IP-2014-09-3386; Title: Dizajn i sinteza novih dušikovih heterocikličkih fluorofora i fluorescentnih nanomaterijala kao kemijskih senzora za pH i metalne ione; Title: Design and Synthesis of Novel Nitrogen-Containing Heterocyclic Fluorophores and Fluorescent Nanomaterials for pH and Metal-Ion Sensing; Acronym: iNFiNiTE–SENS; Leader: Robert Vianello; Jurisdiction: Croatia; Funder: HRZZ; Funding stream: IP
• Study programme: Title: Applied Chemistry - Graduate study; specializations in: Environmental chemistry and green technologies, Advanced materials and technologies, Applied organic chemistry; Course: Applied organic chemistry; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra primijenjene kemije (magistar/magistra primijenjene kemije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Access restricted to students and staff of home institution
• Created on: 2022-02-21 14:18:49